Abstract
The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. However, the mechanisms regulating the 2 HJV isoforms remain unclear. Here we show that s-HJV originates from a furin cleavage at position 332-335. s-HJV is reduced in the cleavage mutant R335Q as well as in cells treated with a furin inhibitor, and increased in cells overexpressing exogenous furin, but not in cells overexpressing an inactive furin variant. Furin is up-regulated by iron deficiency and hypoxia in association with the stabilization of HIF-1alpha. Increased s-HJV in response to HIF-1alpha occurs during differentiation of murine muscle cells expressing endogenous Hjv. Our data are relevant to the mechanisms that relate iron metabolism to the hypoxic response. The release of s-HJV might be a tissue-specific mechanism, signaling the local iron requests of hypoxic skeletal muscles independently of the oxygen status of the liver.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Antimicrobial Cationic Peptides / biosynthesis
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Antimicrobial Cationic Peptides / genetics
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism
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Cell Differentiation / physiology
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Cell Hypoxia / physiology
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Down-Regulation / physiology
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Furin / genetics
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Furin / metabolism*
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GPI-Linked Proteins
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HeLa Cells
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Hemochromatosis Protein
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Hepcidins
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Homeostasis / physiology*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Iron / metabolism*
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Iron Deficiencies
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Iron Overload / genetics
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Iron Overload / microbiology*
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Liver / cytology
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Liver / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Muscle Cells / cytology
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Muscle Cells / metabolism
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Muscle, Skeletal / cytology
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Muscle, Skeletal / metabolism
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Mutation, Missense
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Organ Specificity / physiology
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Oxygen / metabolism
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Signal Transduction / physiology
Substances
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Antimicrobial Cationic Peptides
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Bone Morphogenetic Proteins
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GPI-Linked Proteins
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HAMP protein, human
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HIF1A protein, human
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HJV protein, human
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HJV protein, mouse
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Hamp protein, mouse
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Hemochromatosis Protein
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Hepcidins
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Protein Isoforms
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Iron
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FURIN protein, human
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Furin
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Oxygen